This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. This project started with the laboratory of Dr. Mario Capecchi at the University of Utah's Eccles Institute of Human Genetics. Dr. Capecchi's laboratory was investigating the phenotypic expression of specific, induced genetic abnormalities in mice, a model that has been shown to provide insight into the ontogeny of congenital human disease. Conventional analysis of mouse skeletal structure requires sacrificing the research animal and a labor-intensive, time-consuming process of skeleton preparation and physical inspection under a dissecting microscope. Many tens or even hundreds of specimens are often required for a meaningful statistical analysis, which represents an enormous investment of time and money. The goal of the Center for Integrative Biomedical Computing collaboration with the Capecchi lab is to develop a faster, non-invasive protocol for skeletal analysis that uses semi-automated image processing of three-dimensional micro-CT rather than hand measurements of prepared skeletal specimens. We are continuing the development of a set of image segmentation, measurement and visualization algorithms and software systems for quantitative morphometry that allow us to experiment with new metrics such as the analysis of shape that would not be possible with prepared skeletal specimens. Furthermore, we expect that our tools will allow for more precise and repeatable measurements for length, density and volume, and therefore give insight into genetic alterations that have previously been described as pleiotropic (partially penetrant) or that have been misinterpreted as minor effects. Over the years this project has gained interest from collaborators working with other imaging modalities and various pathologies including childhood tumors, autism, and heart defects. In particular, collaborative work with the Charles Keller laboratory (University of Oregon Health Sciences Center) is extending the shape analysis work. The work of the CIBC with Dr. Keller has focused primarily on skeletal phenotypes using mouse mice models that have been created through genetic knock outs. The process has been to segment sets of 3D microCT images using Seg3D and to analyze and visualize the results using the CIBC software: ShapeWorks, SCIRun and/or ImageVis3D. This work represents an ongoing strategy of reverse genetics in the mouse as a way of determining the contribution of a single gene to a complex biological process, such as developmental patterning.